tbuckley/cabot-search huggingface dataset:
CTNI-42. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS RADIATION IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Nazanin Majd, D Nana Yeboa, Shiao-Pei Weathers, Ying Yuan, Christine Robichaux, Haider Al Anssari, Evguenia Gachimova, Monica Loghin, Carlos Kamiya-Matsuoka, Barbara O'Brien, Ashley Aaroe, Chirag Patel, W K Alfred Yung, Max Wintermark, Maria Gule, Sherise Ferguson, Vinay Puduvalli, John de Groot
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND DNA-dependent protein kinase (DNA-PK) is a pivotal component of DNA damage repair (DDR) pathways and is an attractive target in glioblastoma because its expression renders tumors less vulnerable to radiotherapy. Peposertib is a small molecule DNA-PK inhibitor that has been shown to potentiate radiotherapy and regress glioblastoma tumors pre-clinically. We conducted a two-stage phase I trial of peposertib plus radiation in newly-diagnosed MGMT-unmethylated glioblastoma (NCT04555577). Method: In stage 1, patients received peposertib plus standard-of-care radiotherapy to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design (maximum n = 24). Stage 2 is a window-of-opportunity expansion cohort and will include 5 surgical patients to evaluate tumor drug concentration. Both groups receive adjuvant temozolomide for 6-cycles. RESULTS Fifteen completed the 10-week dose-limiting toxicity (DLT) period; 3-50mg, 3-100mg, 3-200mg, 6-300mg. One DLT (G3 radiation necrosis [RN] at 300mg) was observed. Most notable toxicity was 3 patients with transient G3 dermatitis of the scalp (not DLT per protocol) (2-200mg, 1-300mg). Therefore, radiation dose constrains to the skin were incorporated and subsequent patients did not experience this toxicity. Next-generation sequencing (NGS) was available for 13 archival tissue. Two patients had pathology-proven RN (one within and one outside of the DLT period). Both tumors had mutations in DDR genes (i.e. ATRX, DICER1). Recurrent tissue was available for one patient after treatment with peposertib showed gain of two ATM mutations. CONCLUSION The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of two ATM mutations in a recurrent tumor and the cases of scalp dermatitis suggest that peposertib is active and possibly potentiates the effect of radiation. Safety and survival data and correlations with genomics will be presented. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755).
RADT-46. STEREOTACTIC RADIOSURGERY FOR CYSTIC AND SOLID INTRACRANIAL HEMANGIOBLASTOMAS: A SINGLE-INSTITUTION RETROSPECTIVE SERIES
Authors: Kelly Yoo, David Park, Neelan Marianayagam, Erqi Pollom, Scott Soltys, Antonio Meola, Steven Chang
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Intracranial hemangioblastoma is a rare neoplasm that poses significant challenges in clinical management. Hemangioblastomas are characterized by unique radiological features into cystic or solid tumors. Out study aims to evaluate the role of SRS in the management of cystic and solid hemangioblastomas in a single institution setting. METHODS We conducted a retrospective analysis of clinical and radiological outcomes of patients with intracranial hemangioblastomas treated with CyberKnife SRS at our institute between 1998 and 2023. The follow-up data were available for 93 intracranial hemangioblastomas in 23 patients. Ten (43.5%) patients presented with 23 (25.6%) cystic hemangioblastomas, while 13 (56.5%) patients had 70 (75.3%) solid hemangioblastomas at the time of SRS treatment. The median age was 36 years and the median tumor volume accounted for 0.43 cc. The SRS was administered with the median single-fraction equivalent dose (SFED) of 20 Gy at the 77% of the median isodose line. RESULTS At a one-year follow-up, 11 initially solid hemangioblastomas developed cystic formation, resulting in a total of 34 (36.6%) cystic hemangioblastomas and 59 (63.4%) solid hemangioblastomas across 13 and 10 patients, respectively. Among these, 84.6% exhibited peritumoral edema prior to the onset of cystic formation. For 37 solid hemangioblastomas accompanied by peritumoral edema, SRS was administered before cystic transformation, remaining solid throughout the latest follow-up. Over a median follow-up period of 59 months (range: 3-260), 6 (17.6%) cystic and 13 (22%) solid hemangioblastomas progressed. The 5-year local tumor control (LTC) rate for intracranial hemangioblastomas was 84.7%, with 97% and 76.9% in cystic and solid lesions, respectively. CONCLUSION Our study illustrates the largest single-institutional long-term retrospective analysis of intracranial hemangioblastomas treated with SRS to date. Early SRS treatment at the time of edema may prevent cystic hemangioblastoma development and provides durable treatment outcomes for patients with both cystic and solid hemangioblastomas in long-term.
SURG-10. DEVELOPMENT OF 2 COMPLEMENTARY INNOVATIVE APPROACHES FOR REAL-TIME, LABEL-FREE INTRAOPERATIVE TUMOR DETECTION TO ENHANCE EXTENT OF RESECTION OF LOW GRADE GLIOMAS
Authors: Steven De Vleeschouwer, Eva Cuypers, Laura Van Hese, Tom Theys, Ron Heeren, Roeland Vandebriel, Siri Luthman, Kathleen Vunckx, Murali Jayapali, Wouter Charle, Lien Solie, Tommaso Giannantonio, Anna Alperovich, Xiaohan Zhang
Journal: Neuro-Oncology (2023)

Abstract Brain tumor surgery aims to maximize tumor resection while avoiding neurological deficits. Accurate characterization of tissue and delineation of resection margins are essential to achieve optimal surgical outcome. Hyperspectral imaging (HSI) and Real-time Rapid Evaporative Ionization Mass Spectrometry ( REIMS) are both novel technological adjuncts able to accurately detect intraoperatively zones of low grade glioma without substantially altering the surgical work flow. For HSI, we successfully demonstrate how an HSI system can interface with a clinically approved surgical microscope making use of the microscope’s available light sources and optical ports. We integrated the HSI system into the clinical workflow during brain surgery, specifically for resections of low-grade gliomas (LGG). During the study the acquired dataset was used to train an AI algorithm to detect LGG, providing 81% accuracy on unseen data. Real-time Rapid Evaporative Ionization Mass Spectrometry (REIMS) enables in-situ tissue characterization based on the mass spectrometric analysis of electrosurgical vapors generated during dissection. We demonstrate the use of REIMS for the molecular characterization of brain tumor tissue, thereby providing quasi real-time assessment of tumor type. A classification model containing 31 sampling points in normal brain tissue and 93 in glial tumor tissue provided 89.3% sensitivity and 91.1% specificity. Both techniques, HSI and REIMS display a high intraoperative diagnostic accuracy in terms of glioma tissue detection and are complementary, real-time and label-free methods which we developed and tested up to the stage of high Technology Readiness levels (TRL) of 7 and 5 respectively.
EXTH-49. A NOVEL MULTIVALENT DRUG CONJUGATE FOR HIGH-GRADE GLIOMA TREATMENT
Authors: Waldemar Debinski, Kaitlin N Fink, Denise Herpai, John Rossmeisl
Journal: Neuro-Oncology (2023)

Abstract Interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed collectively in almost all patients with glioblastoma (GBM), and also in spontaneous canine gliomas, the most faithful model of human disease. The four receptors are widely present in various compartments of GBM tumors, including tumor core, infiltrating cells, tumor neovasculature and tumor-associated macrophages. Thus, the four receptors are expressed in several GBM compartments involved in tumor progression and/or resistance to therapies, covering almost 100% of the tumor microenvironment. In first-of-a-kind approach, we performed Phase I clinical trial in dogs with gliomas using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. The cocktail was administered loco-regionally through convection-enhanced delivery, using anti-reflux catheters and real-time MRI monitoring of drugs distribution. We observed prominent anti-tumor responses, including several near complete regressions, prolongation of survival and excellent quality of life, although we did not achieve dose-limiting toxicity (Neuro-Oncol 2021;23(3):422-434). Encouraged by these exceptional results, we pursued the novel idea of targeting the four GBM-associated receptors with one pharmaceutical compound. To this end, we designed, produced, and tested a multivalent ligand binding to all four receptors of our interest, termed QUAD, including murine and canine receptors. However, we found that a conjugate of QUAD with DM1, a microtubule-disrupting agent, demonstrated an extremely high (in low picomolar range) and specific killing potency on GBM cells. The IC50s of QUAD-DM1 are ~50 times higher than that for all other QUAD-based drug conjugates tested thus far, having a favorable toxicity profile in rodents when injected either intracranially or intravenously. QUAD-DM1 has already produced up to 95% tumor reduction in dogs with spontaneous brain tumors. QUAD-DM1 is a highly promising agent for the treatment of human and canine high-grade gliomas.
RADT-04. DOSE PAINTING WITH THE GAMMA KNIFE LIGHTNING OPTIMIZER TO ESCALATE RADIATION DOSE TO RESIDUAL TUMOR WITHIN BRAIN METASTASIS RESECTION CAVITIES
Authors: Andrew Barbour, Evan Gates, Eric Ford, Mark Phillips, Lia Halasz
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The novel Gamma Knife (GK) Lightning optimizer allows simultaneous automated optimization of multiple intracranial radiotherapy targets. We used this optimizer to create a dose-painting treatment plan where an escalated dose was prescribed to residual disease within a brain metastasis resection cavity. We validated this method by measuring dose-delivery accuracy using radiochromic film in an anthropomorphic phantom. METHODS A 15.7cc irregular contour was drawn to represent a brain metastasis resection cavity, a 2mm expansion contour created, and a 1.6cc contour drawn representing a nodule of residual disease. In GammaPlan v11.3.1, three targets were created with overlapping dose matrices. Targets were prescribed 3Gy (2mm expansion), 4Gy (resection cavity), and 5Gy (residual disease) in one fraction. On the GK Icon system, an occipital mold was made, an unexposed film placed in the phantom’s cranium, cone-beam coregistration conducted, and treatment delivered. The film was scanned and calibrated for absolute dosimetry. To evaluate dose-painting accuracy, global gamma index (GI) analyses were performed at various dose and distance tolerances, excluding points below 30% of the maximum dose. RESULTS An 18-minute treatment plan with 40 shots was created and delivered. Prescription isodose lines were 3Gy at 55% (2mm expansion, mean 4.8Gy), 4Gy at 69% (resection cavity, mean 5.2Gy), and 5Gy at 75% (residual disease, mean 6.1Gy). All target volumes had ≥ 99% prescription dose coverage and the maximum dose was 6.9Gy. Paddick conformality indices were 0.79 (2mm expansion), 0.74 (resection cavity), and 0.15 (residual disease). Gamma index pass rate/mean GI/median GI were 73%/0.68/0.55 at 1%/1mm tolerance, 85%/0.58/0.48 at 2%/1mm tolerance, and 97%/0.34/0.28 at 2%/2mm tolerance. An average of 17,883 points were evaluated per analysis. CONCLUSIONS We successfully performed GK dose painting with the Lightning optimizer, verifying dose delivery within clinically acceptable tolerances. Future work is needed to determine optimal dose levels for use in clinical practice.
TMIC-20. A SPATIALLY RESOLVED HUMAN GLIOBLASTOMA ATLAS REVEALS DISTINCT CELLULAR AND MOLECULAR PATTERNS OF ANATOMICAL NICHES
Authors: Nameeta Shah, Hyun Jung Park, Pranali Sonpatki, Kyung Yeon Han, Hyeon Jong Yu, Shin Wook Kim, Tamrin Chowdhury, Yoon Hwan Byun, Ho Kang, Joo Ho Lee, Soon-Tae Lee, Jae-Kyung Won, Tae Min Kim, Seung Hong Choi, Young-Kyoung Shin, Ja-Lok Ku, Sungyoung Lee, Hongseok Yun, Sung Hye Park, Chul-Kee Park, Woong-Yang Park
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly plastic ecosystem where the complex interplay between different cellular components contributes to disease progression. Although single-cell RNA (scRNA)-seq has revealed remarkable cellular heterogeneity of GBM, our knowledge regarding the spatial organization of its cellular components is currently lacking. Here we created a comprehensive dataset of 115,914 spatial transcriptomes across 32 tissue sections with matched multi-omics profiling on a set of genotyped glioma samples. We present spatial maps of 56 fine-grained cellular components, including previously unrecognized subtypes of oligodendrocytes and stromal cells, and their spatial interaction networks in each GBM- associated anatomical niche. Furthermore, the deconvolution of bulk RNA-seq data using the integrated spatial and single-cell atlas revealed clinically relevant GBM ecotypes. Our data provides comprehensive insights into the cellular architecture of GBM at high spatial resolution. It will be a valuable resource to develop effective combinatorial therapies to target all tumor-fostering niches simultaneously.
EPCO-08. CONVERGENCE OF NON-CODING SOMATIC MUTATIONS ON CANCER DRIVER PLEXUSES IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Tina Huey-Miin Chen, Divya Singhal, Marco Gallo
Journal: Neuro-Oncology (2023)

Abstract Central nervous system tumors are the most common pediatric malignancies after leukemia, and the most common cause of cancer death among persons ages 0 – 14 [1,2]. Despite its low incidence rate, pediatric high-grade gliomas (pHGGs) account for over 40% of all childhood brain tumor deaths [3, 4]. As such, it remains the focus of many research teams across the globe. The discovery of recurrent mutations in genes encoding histone H3.3 [5] was a breakthrough in the genetic basis of pHGGs and highlighted the relevance of epigenetic reconfiguration for oncogene activation. However, much work is still needed to uncover driver alterations responsible for tumor initiation or progression. pHGGs have frequent epigenetic dysregulation [6,7] and abundant somatic mutations in the noncoding regions of the genome [8], but the functional relevance of the noncoding somatic mutations has not been evaluated systematically. Here, we assess correlations between noncoding somatic mutations in pediatric brain-specific cis-regulatory elements (CREs) and changes in gene expression. We demonstrate the sparsity of recurrent mutations in CREs. Then illustrate the power of graph database in consolidating multi-omics datasets for efficient queries. Our network approach for charting the genomic, epigenetic, and transcriptomic landscape of pHGG allow us to 1) identify clusters of CREs associated with dysregulated gene expression, 2) nominate transcription factors whose binding affinities are recurrently impacted by somatic mutations found in pHGGs, and 3) establish regulatory networks potentially guiding pHGG tumor growth and progression.
SURG-26. HYDROCEPHALUS IN LEPTOMENINGEAL DISEASE: TANDEM OMMAYA RESERVOIR-SHUNT FOR INTRATHECAL CHEMOTHERAPY ADMINISTRATION
Authors: Amber Valeri, Arnold Etame, Andre Beer-Furlan, James Liu, Hsiang-Hsuan Michael Yu, Daniel Oliver, Yolanda Pina, Michael A Vogelbaum, Peter Forsyth, Sepideh Mokhtari, Solmaz Sahebjam, Nam Tran
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Leptomeningeal disease (LMD) is a rare late-stage manifestation of disease progression in solid and hematologic malignancies. Although advances in intrathecal therapeutic (IT) provide treatment options beyond the traditional WBRT, these IT treatment strategies are limited when LMD patients develop associated hydrocephalus. CSF shunting can improve quality of life but may lead to decreased exposure time of IT therapies, with overall survival remaining less than 4 months. Our institution implemented placement of an Ommaya reservoir with ventricular shunt for administration of intrathecal chemotherapy while allowing for concomitant CSF diversion. METHODS The authors performed a retrospective chart review on all patients who underwent placement of Ommaya reservoir with a ventricular shunt for treatment of hydrocephalic LMD from Sept 2011 to Feb 2021. LMD secondary to primary glial neoplasm were excluded. Patient demographics, clinical characteristics, tumor characteristics, systemic and IT chemotherapy regimen, length of survival and complications were assessed. RESULTS Forty-one patients were included in the study: 18 breast, 12 lung, 5 melanoma, 2 gastric, 2 diffuse large B cell lymphoma, 1 AML, 1 pancreatic. 33.3% of breast cancer were HER-2 positive, while 40% melanoma were BRAF mutated. Patients receiving IT + shunt and WBRT (n = 22) had mean survival time of 350 days from LMD diagnosis compared with 182 days for shunt and WBRT alone (n = 19; p = 0.07). Breast and melanoma patients with IT (n = 16) had improved survival compared with patients with shunt and WBRT (n = 7) alone (419 vs 91 days, p = 0.03). Kaplan-Meier survival analysis demonstrates a positive trend towards increased survival in IT + shunt and WBRT group. CONCLUSION This treatment strategy of Ommaya reservoir and shunt prolongs survival in patients with LMD and associated elevated intracranial pressures. This may be very important as we enter the era of cellular immunotherapies for LMD.
BIOM-14. INCREASED RATIO OF GLUTAMATE TO TOTAL CREATINE IN GLIOBLASTOMA PATIENTS WITH THE POST-OPERATIVE EPILEPSY
Authors: Kazuhiro Tanaka, Mitsuru Hashiguchi, Shunsuke Yamanishi, Hiroaki Nagashima, Takashi Sasayama
Journal: Neuro-Oncology (2023)

Abstract Epilepsy in glioblastoma patients significantly reduces their quality of life; however, little is known about the association between predicting epilepsy and metabolites in tumors. In this study, we used 3.0-T magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) to quantify metabolite concentrations in patients with varying epilepsy histories. MRS data were quantified with linear combination model (LC-Model) software. From January 2013 to April 2020, fifty-one patients with primary glioblastoma underwent pretreatment 3.0-T MRI/1H-MRS scanning. Twenty-one patients (41%) suffered from epilepsy during the postoperative course, although forty-seven patients (97%) took anti-epileptic drug after surgery. MRS data were compared between groups with and without the post-operative epilepsy. The higher ratios of glutamate (Glu) and glutamate + glutamine (Glx) to total creatine (tCr) in the tumor were significantly associated with epilepsy history (Glu/tCr P &amp;lt; 0.001, Glx/tCr P = 0.004, respectively). The receiver operating characteristic curve analysis showed that a Glu/tCr value of 1.81 was 70% sensitive and 90% specific for the prediction of epilepsy during the postoperative course (area under curve: 0.82). These results suggest that the Glu/tCr ratio in tumors can be a predictive maker for early detection of epileptic seizures after surgery in glioblastoma patients.
CSIG-29. CLINICAL AND TRANSCRIPTOMIC DATASET IDENTIFIES LARGE CHANGES IN IMMUNE AND HORMONAL SIGNALING AMONGST RECURRENT PATIENTS WITH CRANIOPHARYNGIOMA
Authors: Nikhil Joshi, Julia Crowley, Shana Mccormack, Fatema Malbari, Adam Kraya, Cassie Kline
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Craniopharyngioma is a low-grade suprasellar brain tumor that often produces deficiencies of pituitary hormones, including growth hormone. Although epidemiological data are reassuring that growth hormone does not lead to craniopharyngioma recurrence, the theoretical risk is cause for concern. To address this and other questions related to the care of individuals with recurrent craniopharyngioma, we analyzed gene expression in craniopharyngiomas in the context of clinical data. We envision insights that could guide decisions about hormone replacement and tumor-focused treatment alternatives. METHODS Clinical information was abstracted for a cohort of individuals diagnosed with craniopharyngioma at the Children’s Hospital of Philadelphia between 2016 - 2020. In parallel, tumor transcriptomic data for patients with craniopharyngioma were collected from the Children’s Brain Tumor Network (CBTN) and matched to clinical data where applicable. Bulk RNA-sequencing analysis, pathway analysis, and immune deconvolution (xCell) of samples was performed in R to identify transcript-level changes that distinguish recurrent from initial craniopharyngioma. RESULTS CBTN data was available for 54 initial tumor samples and 17 recurrent tumor samples, with matched clinical data available for 33 samples (26 initial, 7 recurrent). We did not find differences in clinical characteristics between individuals with versus without recurrence. Pathway analysis notably suggested altered levels of antigen presentation (NES: 2.97), Programmed cell death (NES: 2.34), WNT signaling (NES: 1.97), and Growth Hormone Signaling (NES: -1.277) amongst recurrent samples when compared against initial samples. Deconvolution of samples showed altered levels of M2-like macrophages (39.2% increased) and CD4+ T-helper-2 cells (-54.7% decreased) in recurrent samples compared against initial samples. Preliminary work is being completed to frame these results in the context of available clinical neuroendocrine data. CONCLUSION This work highlights marked changes in immune and hormonal signaling in samples from recurrent craniopharyngioma tumors. These insights have potential therapeutic implications that deserve further investigation.
EPCO-10. AN ONCOGENIC NEURODEVELOPMENTAL PROGRAM IN H3.3 K27M DIFFUSE MIDLINE GLIOMA INVOKES ABERRANT ASCL1-SMARCA4 EPIGENOMIC ACTIVITY
Authors: Paul Knoepfler, Rachel Klein, Jennifer Yee, Nichole Lewis
Journal: Neuro-Oncology (2023)

Abstract The histone variant H3.3 K27M mutation is common in diffuse midline gliomas (DMG) and is associated with poor prognosis. While some insights into K27M epigenetic functions have emerged, much less is known about how K27M impacts chromatin structure and function, and the resulting transcriptomic consequences. Recently, we developed isogenic CRISPR-edited DMG cell lines that are wild-type for histone H3.3 that can be compared to their matched K27M lines. ATAC-seq analysis of the matched sets of isogenic WT and H3.3K27M glioma cells pointed to unique K27M-associated accessible chromatin at regions corresponding to specific neurogenesis, NOTCH, and neuronal development pathways. These domains corresponded to genes that are overexpressed in H3.3K27M compared to our isogenic wild-type cell lines. Uniquely accessible enhancers and super-enhancers corresponding to increased gene expression in H3.3K27M cells were also mapped to genes involved in neurogenesis and NOTCH signaling, suggesting that these pathways are important for tumorigenesis. Motif analysis implicates specific transcription factors as central to the neuro-oncogenic K27M signaling pathway including, in particular, ASCL1 and NEUROD1. CUT&amp;RUN for ASCL1 defined novel target genes in DMG and BioID identified key epigenomic cofactors for ASCL1 including SMARCA4. Large-scale computational analysis of both our and other groups’ data including by chromHMM identified novel functional chromatin domains and potential looping events related to K27M as well. Overall, our findings indicate that H3.3K27M changes specific chromatin functions altering neurodevelopmental gene expression resulting in aberrant activity of an oncogenic epigenomic program. Encouragingly, this program appears at least partially reversible upon editing K27M back to wild-type, pointing to potential translational impact moving forward to targeting this pathway.